Epicutaneous Immunotherapy Research Articles

Efficacy and Safety of Epicutaneous Immunotherapy (EPIT) for Peanut Allergy in Subjects Aged 1-3 Years With and Without Concomitant Food Allergies in the EPITOPE Study

Efficacy and Safety of Epicutaneous Immunotherapy (EPIT) for Peanut Allergy in Subjects Aged 1-3 Years With and Without Concomitant Food Allergies in the EPITOPE Study

Epicutaneous Immunotherapy with CBir1 Alleviates Intestinal Inflammation.

Inflammatory bowel disease may be due to failed tolerance to normal gut bacteria. We demonstrate that epicutaneous immunotherapy (ET) to ovalbumin can alleviate colitis in murine models. However, most people are tolerant to or have anergy to ovalbumin. Half of Crohn's disease (CD) patients have CBir1 antibodies that can be elevated years before CD development. We determined whether ET with a CBir1 multi-epitope peptide (MEP1) could alleviate colitis. Wild type mice (C57BL/6) were transferred with CBir1 T cell receptor (TCR) T cells followed by epicutaneous application of MEP1. Proliferating Foxp3+ T cells were measured in mesenteric lymph nodes (LNs), spleen, small intestine, and colon by flow cytometry. Lymphocytes from MEP1 epicutaneously exposed and immunized C57BL/6 mice were cultured with MEP1. Interferon (IFN)-γ production was measured. Colitis was induced by transferring CD4+CD45Rbhi T cells from CBIR1 TCR or C57BL/6 mice into RAG1-/- mice. Mice were treated with ET. Body weight, colon length, colonic cytokine production, histological inflammation, inflammatory genes, and regulatory T cells (Tregs) from lamina propria were measured. ET with 10 μg of MEP1 induced CBir1-specific Tregs that migrated to the small intestine and colon and suppressed MEP1-specific IFN-γ production. ET alleviated colitis when the model utilized CBir1 TCR T cells in mice colonized with CBir1 or A4Fla2 positive bacteria. Treated mice had improved colon length and histological inflammation and reduced colonic IFN-γ production. Epicutaneous immunotherapy with MEP1 induced Tregs that migrate to intestines and suppress inflammation in mice with CBir1 or A4Fla2-positive bacterial colonization. This could be a potential strategy to treat CD and warrants further study.

Celebrating the 15th Anniversary ofImmunotherapy: A Reflection on 2022

Celebrating the 15th Anniversary of<i>Immunotherapy</i>: A Reflection on 2022

EPITOPE STUDY RESULTS: PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF EPICUTANEOUS IMMUNOTHERAPY IN PEANUT-ALLERGIC TODDLERS

<h3>Introduction</h3> No approved peanut allergy treatments exist for children <4 years old. This study aimed to assess the efficacy and safety of epicutaneous immunotherapy with a patch containing 250 µg peanut protein among peanut-allergic children ages 1-3 years. <h3>Methods</h3> In a Phase 3, multicenter, randomized, double-blind, placebo-controlled trial (EPITOPE), peanut-allergic children developing symptoms meeting stopping criteria during double-blind, placebo-controlled food challenge (DBPCFC) at an eliciting dose (ED) ≤300 mg peanut protein were randomized 2:1 to 12 months of daily treatment with the peanut patch (n=244) or placebo patch (n=118). The primary outcome was the percent difference in responders between active and placebo, determined by DBPCFC ED at baseline and Month 12. Safety was assessed by treatment-emergent adverse event (TEAE) rate. <h3>Results</h3> Of 362 participants randomized (median age: 2.5 years, 68.8% male), 84.8% completed treatment. The primary efficacy endpoint was met by 67% receiving active peanut patch vs. 33.5% receiving placebo (difference=33.4%; 95% CI: 22.4–44.5% [p<i><</i>0.001]). Additionally, 64.2% active vs. 29.6% placebo recipients (difference=34.7%; [p<i><</i>0.001]) achieved a peanut protein ED ≥1000 mg. The majority of TEAEs were mild or moderate application site reactions. Serious TEAEs occurred in 8.6% peanut patch vs. 2.5% placebo recipients, with 1.6% (n=4) peanut patch subjects experiencing treatment-related anaphylaxis, and 3.3% (n=8) peanut patch subjects discontinuing due to a TEAE. <h3>Conclusions</h3> Twelve months of epicutaneous immunotherapy with a patch containing 250 µg peanut protein was associated with a statistically significant response vs. placebo among peanut-allergic children aged 1-3 years. Rates of treatment-related anaphylaxis and discontinuations due to TEAEs were low.

Reduction in Reaction Severity Following 12 Months of Epicutaneous Immunotherapy with Peanut Patch in Toddlers

<h3>Introduction</h3> In a recent Phase 3 clinical trial (EPITOPE), treatment with a peanut patch containing 250 µg peanut protein for 12 months was statistically superior to placebo in desensitizing peanut-allergic children aged 1-3 years, with 67% vs 33.5% being treatment responders (difference: 33.4%; 95% CI: 22.4, 33.5 [p<0.001]). The ability of the peanut patch to reduce reaction severity, a major goal of allergen immunotherapy, was also characterized in a pre-specified analysis. <h3>Methods</h3> Double-blind, placebo-controlled food challenges (DBPCFC) were performed at baseline and Month 12 to determine eliciting dose (ED). Standardized DBPCFCs were stopped only after sufficient signs/symptoms, in accordance with PRACTALL guidelines. Symptoms in each body system were graded by prespecified criteria (scored 0-3). Maximum severity of symptoms at baseline and Month 12 between active and placebo groups was compared. <h3>Results</h3> At baseline, there was a similar proportion of mild/moderate/severe signs/symptoms between active and placebo (p=0.911). At baseline, an equal percentage of subjects in the active and placebo groups (24.6% in each group) had a maximum symptom severity score of 3 ("severe"). At Month 12, there was a significant difference between groups in maximum symptom severity (p<0.001), with 12.5% of active subjects having a symptom severity score of 3 ("severe") compared with 28.6% in placebo. At Month 12, 36.5% of active subjects had no or mild symptoms compared with 20.4% of placebo. <h3>Conclusion</h3> This analysis suggests that, in addition to achieving desensitization in 1-3-year-old peanut-allergic children, EPIT with a patch containing 250 µg peanut protein may also reduce the severity of allergic reactions.

Food allergy: History, definitions and treatment approaches.

Allergen-specific immunotherapy for the treatment of immunoglobulin E mediated food allergies, specifically oral, epicutaneous, and sublingual immunotherapies, are promising options that may provide an alternative to strict avoidance of the dietary allergen. Of these potential therapies, oral immunotherapy is the furthest along in development, with strong evidence of efficacy in clinical trials, and has achieved regulatory approval. Nevertheless, oral immunotherapy may not be a suitable therapy for some patients due to the risk of adverse effects. In contrast to oral immunotherapy, epicutaneous and sublingual immunotherapies have demonstrated modest efficacy in clinical trials, with a favorable adverse effect profile, which suggests that these therapies may be possible contenders to oral immunotherapy in certain clinical situations. Familiarity with the various treatment approaches is vital for guiding patients and families as more therapeutic modalities become available for use outside of the research setting.

Future directions in allergen immunotherapy.

Both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) are effective clinically against allergic rhinitis and allergic asthma, and modify the underlying immunologic abnormalities. Despite this, many patients who could benefit from receiving SCIT and SLIT do not because of concerns about safety and the inconvenience in receiving SCIT, and the long duration of treatment with both, 3-4 years being required for lasting benefit. Attempts to improve the efficacy and safety, and to shorten the course of allergen immunotherapy have taken many approaches. Some approaches have generated great enthusiasm, only to fail in larger trials and be discarded. Other approaches show some promise but perhaps not enough to achieve regulatory approval. Those approaches that seem to have the best chance of becoming available in the next few years include the following: intralymphatic and epicutaneous immunotherapy, vitamin D in patients with insufficient serum 25 hydroxy vitamin D, probiotics, and allergoids, but all require further studies before being ready for nonexperimental use or, where necessary, for regulatory approval.

Epicutaneous allergen immunotherapy induces a profound and selective modulation in skin dendritic-cell subsets

Epicutaneous immunotherapy (EPIT) protocols have recently been developed to restore tolerance in patients with food allergy. The mechanisms by which EPIT protocols promote desensitization rely on a profound immune deviation of pathogenic T- and B-cell responses. To date, little is known about the contribution of skin dendritic cells (skDCs) to T-cell remodeling and EPIT efficacy. We capitalized on a preclinical model of food allergy to ovalbumin (OVA) to characterize the phenotype and functions of OVA⁺ skDCs throughout the course of EPIT. Our results showed that both Langerhans cells and dermal conventional cDC1 and cDC2 subsets retained their ability to capture OVA in the skin and to migrate toward the skin-draining lymph nodes during EPIT. However, their activation/maturation status was significantly impaired, as evidenced by the gradual and selective reduction of CD86, CD40, and OVA protein expression in respective subsets. Phenotypic changes during EPIT were also characterized by a progressive diversification of single-cell gene signatures within each DC subset. Interestingly, we observed that OVA⁺ Langerhans cells progressively lost their capacity to prime CD4⁺ T_EFF cells, but gained regulatory T-cell stimulatory properties. In contrast, cDC1 were inefficient in priming CD4⁺ T_EFF cells or in reactivating T_MEM cells invitro, whereas cDC2 retained moderate stimulatory properties, and progressively biased type 2 immunity toward type 1 and type 17 responses. Our results therefore emphasize that the acquisition of distinct phenotypic and functional specializations by skDCs during EPIT is at the cornerstone of the desensitization process.

Psychometric parameters of food allergy quality of life during an allergen immunotherapy trial.

BackgroundThe Food Allergy Quality of Life Questionnaire–Parent Form (FAQLQ‐PF) is a commonly used patient‐reported outcome measure in food allergy (FA) research. It was developed before FA treatment clinical trials were commonplace and is used as a secondary outcome measure in pivotal FA treatment trials. We examined the psychometric properties of the FAQLQ‐PF and its relevance to children with peanut allergy engaged in an epicutaneous immunotherapy (EPIT) clinical trial.MethodsAnalysis was performed on 26 universally answered items of the FAQLQ‐PF, from assessments undertaken during the phase 3 PEPITES study (baseline, Month 12), which examined the safety and efficacy of EPIT for children with peanut allergy aged 4–11 years. Item response theory (IRT) was used to assess psychometric parameters of the FAQLQ‐PF (i.e., discrimination, difficulty, and information). Confirmatory factor analysis was also employed; reliability was assessed using McDonald's omega (ω) and Cronbach's alpha (α).ResultsA total of 23 of 26 items presented very high discrimination levels (>1.7), and all 26 fell within the recommended difficulty threshold (between −1.5 and 1.5). The items contributed a reasonable information level for their respective factors/subdomains. The measure also presented a marginally acceptable model fit for the 3‐factor structure (e.g., comparative fit index = 0.88, Tucker–Lewis index = 0.87) and good reliability levels across time points (ω and α > 0.90).ConclusionsHerein, we present a novel reanalysis of the FAQLQ‐PF items using IRT. The longitudinal performance of individual items and subscales was corroborated, and items with the highest discrimination were identified, showing that the tool is suitable for longitudinal measurements in FA treatment trials.

Molecular interface between food allergy diagnosis and treatment: Value of a multi-omics approach

Due to the ever-increasing prevalence of Food Allergy (FA) in the United States, many studies have been conducted to better understand mechanisms of Food Allergy, diagnosis, and treatment. Traditional diagnosis of FA can be time-consuming, less dependable, and can lead to severe allergic reaction in some patients. In this review, the latest evidence on testing, appropriate biomarkers for diagnosis, and treatment options are presented. The benefits of trained immunity (TRIM), oral immunotherapy (OIT), sublingual immunotherapy (SLIT), and Epicutaneous immunotherapy (EPIT) are discussed in this review as well. Common biomarkers of food allergies are discussed, including 2S albumins, T-cells, and basophil activation markers. The benefits of a multi-omics approach are highlighted by the complex nature of food allergies and the relationship between genes, proteins, metabolites, and the microbiome in response to allergens. Future possibilities of omics studies pertaining to food allergies are also presented to guide future research.

World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow’s Milk Allergy (DRACMA) Guideline update – XIV – Recommendations on CMA immunotherapy

BackgroundThe prevalence of cow's milk allergy (CMA) is approximately 2–4.5% in infants and less than 0.5% in adults. Most children outgrow cow's milk allergy in early childhood, particularly that to the baked milk products. Immunotherapy with unheated cow's milk has been used as a treatment option for those who have not yet outgrown CMA, but the benefits must be balanced with the adverse effects. ObjectiveThese evidence-based guidelines from the World Allergy Organization (WAO) intend to support patients, clinicians, and others in decisions about the use of oral and epicutaneous immunotherapy for the treatment of IgE-mediated CMA. MethodsWAO formed a multidisciplinary guideline panel balanced to include the views of all stakeholders and to minimize potential biases from competing interests. The McMaster University GRADE Centre supported the guideline-development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used, including GRADE Evidence-to-Decision frameworks, which were subject to public comment. ResultsAfter a careful review of the summarized evidence and thorough discussions the WAO guideline panel suggests: a) using oral immunotherapy with unheated cow's milk in those individuals with confirmed IgE-mediated CMA who value the ability to consume controlled quantities of milk more than avoiding the large adverse effects of therapy, b) not using oral immunotherapy with unheated cow's milk in those who value avoiding large adverse effects of therapy more than the ability to consume controlled quantities of milk, c) using omalizumab in those starting oral immunotherapy with unheated cow's milk, d) not using oral immunotherapy with baked cow's milk in those who do not tolerate both unheated and baked milk, and e) not using epicutaneous immunotherapy outside of a research setting. The recommendations are labeled “conditional” due to the low certainty about the health effects based on the available evidence. ConclusionsClinicians, patients, and their family members might want to discuss all the potential desirable and undesirable effects of oral immunotherapy for IgE-mediated CMA and integrate them with the patients' values and preferences before deciding on a treatment option. More robust research is needed to determine with greater certainty which interventions are likely to be the most beneficial with the least harms, and to develop safer, low-cost, and equitable treatments.

Targeted allergen-specific immunotherapy within the skin improves allergen delivery to induce desensitization to peanut.

Aim: Epicutaneous immunotherapy (EPIT) with peanut has been demonstrated to be safe but efficacy may be limited by allergen uptake through the skin barrier. To enhance allergen uptake into the skin, the authors used peanut-coated microneedles and compared them with EPIT in a peanut allergy mouse model. Methods: Sensitized mice were treated with peanut-coated microneedles or peanut-EPIT and then challenged with peanut to determine protection. Results: Treatment with peanut-coated microneedles was safe and showed enhanced desensitization to peanut compared with peanut-EPIT administered via a similar schedule. Protection was associated with reduced Th2 immune responses and mast cell accumulation in the intestine. Conclusion: Peanut-coated microneedles have the potential to present a safe method of improving allergen delivery for cutaneous immunotherapy.

Immunotherapy Effectiveness in Treating Peanut Hypersensitivity: A Systemic Review.

Peanut hypersensitivity is one of the top causes of food-related allergic responses and death in high-income countries. As a result, the goal of this study was to see if various forms of immunotherapies can help reduce the severity of peanut hypersensitivity reactions.From 2019 to 2021, a systematic search of PubMed, Web of Science, Wiley online library, and Science Direct was done. Peanut immunotherapy (PIT) clinical trials were considered. There were 19 trials with a total of 1565 participants. Twelve were on oral immunotherapy (OIT), two on sublingual immunotherapy (SLIT), two on subcutaneous immunotherapy (SCIT), two on epicutaneous immunotherapy (EPIT), and one was a comparison of SLIT and OIT.Desensitization was achieved by 74.3% of those who received OIT, 11% of those who received SLIT, 61% of those who received SCIT, and 49% of those who received EPIT. The majority of adverse events (AE) were mild to moderate. Those requiring epinephrine, on the other hand, were moderate to severe and were more common in the therapy groups.This systematic review showed that the current PIT regimens can accomplish desensitization regardless of the route of administration, with an acceptable safety profile.

Pooled Safety Data from Phase 3 Studies of Epicutaneous Immunotherapy for Peanut Allergy in Children Aged 4-11 Years

Epicutaneous immunotherapy with Viaskin Peanut 250 μg (VP250) has been studied in phase 3 clinical trials: PEPITES, a 12-month, randomized double-blind controlled trial (RDBCT) with an open-label extension (PEOPLE) and REALISE, a 6-month RDBCT followed by an open-label extension. We present pooled safety study data from subjects who received up to 36 months of VP250 treatment.

Allergen immunotherapy and/or biologicals for IgE-mediated food allergy: A systematic review and meta-analysis.

BackgroundThere is substantial interest in immunotherapy and biologicals in IgE‐mediated food allergy.MethodsWe searched six databases for randomized controlled trials about immunotherapy alone or with biologicals (to April 2021) or biological monotherapy (to September 2021) in food allergy confirmed by oral food challenge. We pooled the data using random‐effects meta‐analysis.ResultsWe included 36 trials about immunotherapy with 2126 mainly child participants. Oral immunotherapy increased tolerance whilst on therapy for peanut (RR 9.9, 95% CI 4.5.–21.4, high certainty); cow's milk (RR 5.7, 1.9–16.7, moderate certainty) and hen's egg allergy (RR 8.9, 4.4–18, moderate certainty). The number needed to treat to increase tolerance to a single dose of 300 mg or 1000 mg peanut protein was 2.Oral immunotherapy did not increase adverse reactions (RR 1.1, 1.0–1.2, low certainty) or severe reactions in peanut allergy (RR 1,6, 0.7–3.5, low certainty), but may increase (mild) adverse reactions in cow's milk (RR 3.9, 2.1–7.5, low certainty) and hen's egg allergy (RR 7.0, 2.4–19.8, moderate certainty). Epicutaneous immunotherapy increased tolerance whilst on therapy for peanut (RR 2.6, 1.8–3.8, moderate certainty). Results were unclear for other allergies and administration routes.There were too few trials of biologicals alone (3) or with immunotherapy (1) to draw conclusions.ConclusionsOral immunotherapy improves tolerance whilst on therapy and is probably safe in peanut, cow's milk and hen's egg allergy. More research is needed about quality of life, cost and biologicals.

Recent Advances in Allergen-Specific Immunotherapy in Humans: A Systematic Review.

Allergen-specific immunotherapy (AIT) is presumed to modulate the natural course of allergic disease by inducing immune tolerance. However, conventional AITs, such as subcutaneous immunotherapy and sublingual immunotherapy, require long treatment durations and often provoke local or systemic hypersensitivity reactions. Therefore, only <5% of allergy patients receive AIT as second-line therapy. Novel administration routes, such as intralymphatic, intradermal and epicutaneous immunotherapies, and synthetic recombinant allergen preparations have been evaluated to overcome these limitations. We will review the updated views of diverse AIT methods, and discuss the limitations and opportunities of the AITs for the treatment of allergic diseases in humans.

Proteomics for Development of Food Allergy Vaccines.

Food allergy is a hypersensitivity reaction to food products initiated by immunologic mechanisms, which represents one of the major concerns in food safety. New therapies for food allergies including oral and epicutaneous allergen-specific immunotherapy are required, and B cell epitope-based allergy vaccines are a good promise to improve this field. In this chapter, we describe a workflow for the design of food allergy vaccines using proteomic tools. The strategy is defined based on the characterization of B cell epitopes for a particular food allergen. For that, the workflow comprises five consecutive steps: (1) shotgun proteomics analysis of different protein isoforms for a particular food allergen, (2) downloading all protein sequences for the specific allergen included in UniProtKB database, (3) analysis by protein-based bioinformatics of B cell epitopes, (4) synthesizing of the selected B cell peptide epitopes, and (5) performing of immunoassays using sera from healthy and allergic patients. The results from this method provide a rationale repository of B cell epitopes for the design of new specific immunotherapies for a particular food allergen. The strategy was optimized for all the beta-parvalbumins (β-PRVBs), which are considered as the main fish allergens. Using this workflow, a total of 35 peptides were identified as B cell epitopes, among them the top 4 B cell peptide epitopes that may induce protective immune response were selected as potential peptide vaccine candidates for fish allergy.

Improvements in Quality of Life in Children Following Epicutaneous Immunotherapy (EPIT) for Peanut Allergy in PEPITES and PEOPLE Studies

Peanut allergy is associated with impaired food allergy quality of life (FAQL). Food allergy quality of life questionnaires (FAQLQs) are used to provide insight into the burdens associated with food allergy and may be used as an outcome measure instrument. In the current study, researchers examined FAQL changes after treatment with epicutaneous immunotherapy (EPIT) for peanut allergy.Data from children between the ages of 4 to 11 years who completed 12 months of therapy during the phase 3 Peanut EPIT Efficacy and Safety Study (PEPITES) and the first 12 months of the follow-on open-label extension study PEPITES Open-Label Extension Study (PEOPLE) were included in this study. PEPITES was a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of the epicutaneous peanut patch (DBV712 250μg) in 356 children. Enrolled patients had physician-diagnosed peanut allergy and reacted to ≤300 mg of peanut protein on entry double-blind placebo-controlled food challenge (DBPCFC). Participants were randomly assigned 2:1 to receive a DBV712 250μg epicutaneous peanut patch or placebo patch daily for 12 months. The PEOPLE study is designed to evaluate the long-term safety, tolerability, and efficacy of DBV712 250 μg for up to 5 years of treatment. A total of 298 children enrolled in the PEOPLE study.FAQL was prospectively measured at baseline, month 12 (before DBPCFC, with treatment allocation blinded), and month 24 (before DBPCFC for children initially randomly assigned to placebo, with treatment unblinded) by using the Food Allergy Quality of Life Questionnaire Parent Proxy Form (FAQLQ-PF) for children aged ≤12 years, and the Food Allergy Quality of Life Questionnaire Child Form (FAQLQ-CF) for children aged ≥8 years. FAQL assessments were assessed by analysis of covariance, according to between-group and in-group differences by longitudinal controlled repeated-measure analysis. FAQL assessments were also analyzed post hoc by linear regression analysis by using changes in mean and domain-specific FAQLQ-PF and FAQLQ-CF scores from baseline to month 24 as the dependent variable and treatment group and month 12 FAQLQ assessments as independent variables.FAQLQs were analyzed from placebo (FAQLQ-PF: 96; FAQLQ-CF: 47) and treatment participants (FAQLQ-PF: 209; FAQLQ-CF: 105). At 24 months, global FAQL scores were significantly improved in the treatment group (least squares mean [LSM]: 0.34 [P = .008] and 0.46 [P = .023]). At 24 months, there were significant FAQLQ-PF score improvements in patients initially randomly assigned to treatment who met the efficacy primary end point (n = 74; LSM: 0.55 [P < .001]) and in participants with any eliciting dose (ED) increase (n = 127; LSM, 0.66; P < .001). Improvements in FAQLQ-PF were observed in social dietary limitations, food-related anxiety, and emotional impact domains. Improvements in FAQLQ-CF were observed in risk of accidental exposure and allergen avoidance domains.EPIT was associated with significant global and domain-specific FAQL improvement, largely driven by increases in ED.These findings suggest that EPIT had a meaningful impact on the lives of patients and caregivers. Although there may be some bias toward positive survey responses from caregivers and patients who were satisfied with their outcomes, this encouraging study reveals a measurable modality for capturing outcome perceptions. Additional study of ongoing peanut EPIT is needed to better understand the clinical relationship between intermediate and long-term ED changes, efficacy, safety, and FAQL.

A Synopsis of the Synopses, 2020–2021

A Synopsis of the Synopses, 2020–2021

Safety of Epicutaneous Immunotherapy in Peanut-Allergic Children: REALISE Randomized Clinical Trial Results

Treatment options for peanut allergy are limited. In previous clinical trials, epicutaneous immunotherapy with a patch containing 250-μg peanut protein (Viaskin Peanut 250 μg [VP250]) was well tolerated and statistically superior to placebo in desensitizing peanut-allergic children. To examine the safety of VP250 in children, using a study design approximating potential real-world use. REAL LIfe Use and Safety of EPIT (REALISE) is a phase 3 multicenter study consisting of a 6-month, randomized, double-blind, placebo-controlled period followed by open-label active treatment. Children aged 4 to 11 years with physician diagnosis of peanut allergy received daily treatment with placebo (6 months) or VP250 (up to 36 months). Data from the 6-month, randomized, controlled phase of REALISE are reported. Three hundred ninety-three children were randomized 3:1 to receive VP250 (n= 294) or placebo (n= 99) for 6 months; 284 (72.3%) children had a history of peanut anaphylaxis. According to parent diary, all participants receiving VP250 and 83.8% receiving placebo reported at least 1 episode of local skin reaction, with frequency decreasing over time. Only 4 participants (1.4%) receiving VP250 discontinued because of adverse events (AEs). Epinephrine was administered for allergic reactions attributed to VP250 in 7 children (2.4%), of whom 5 remained in the study; none involved severe anaphylaxis. Overall, AE rates were similar among participants with and without a history of peanut anaphylaxis. In a study designed to mirror real-world use, VP250 was observed to be well tolerated in peanut-allergic children, consistent with previous phase 2b and 3 studies.